HHS Public Access

Author manuscript
J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
Author Manuscript

Published in final edited form as:

J Dev Behav Pediatr. 2017 May ; 38(4): 249–259. doi:10.1097/DBP.0000000000000436.

Neurocognitive correlates of ADHD symptoms in children born

at extremely low gestational age
Megan N. Scott, Ph.D.,
Department of Psychiatry and Behavioral Neuroscience, The University of Chicago Medicine,
Chicago IL, USA

Scott J. Hunter, Ph.D.,

Author Manuscript

Department of Psychiatry and Behavioral Neuroscience, The University of Chicago Medicine,

Chicago, IL

Robert M. Joseph, Ph.D.,

Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA

T. Michael O’Shea, M.D., M.P.H.,

Division of Neonatology, Department of Pediatrics, University of North Carolina School of
Medicine, Chapel Hill NC

Stephen R Hooper, Ph.D.,

Department of Allied Health Sciences, University of North Carolina School of Medicine, Chapel
Hill NC
Author Manuscript

Elizabeth N. Allred, M.S.,

Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston MA

Alan Leviton, M.D., and

Department of Neurology Research, Boston Children’s Hospital and Harvard Medical School,
Boston MA, USA

Karl Kuban, M.D., S.M.Epi.

Division of Pediatric Neurology, Boston Medical Center and Boston University School of Medicine,
Boston, MA, USA

Abstract
Objective—Compared to children born near term, those born extremely preterm are at much
Author Manuscript

higher risk for Attention Deficit Hyperactivity Disorder (ADHD). Little information is available
about differences in neuropsychological outcomes among extremely preterm children with and
without ADHD. The primary aim of our analyses was to evaluate the neuropsychological
correlates of ADHD symptoms in extremely low gestational age newborns (ELGANs).

Corresponding author: Megan N. Scott, University of Chicago, MC3077, 5841 S. Maryland Ave., Chicago, IL 60637,
mnscott@uchicago.edu; telephone: 773-834-5333; fax : 773-702-9929.
Conflicts of Interest: For the remaining authors none were declared.
 Scott et al. Page 2

Method—We obtained Child Symptom Inventory-4 (CSI-4) reports from parents (n = 871) and
Author Manuscript

teachers (n = 634) of 10-year old children born before the 28th week of gestation. The children
completed standardized assessments of neurocognitive and academic functioning.

Results—In the total sample, children who screened positive for ADHD symptoms were at
increased risk for neurocognitive limitations compared to ELGANs who did not meet for ADHD
classification. These associations were weaker when the sample was limited to those with IQ ≥ 70
or those with IQ ≥ 85. Even the children with IQ ≥ 70 and those with IQ ≥ 85 who screened
positive for ADHD symptoms were more likely than their peers to have deficits on the DAS-II
assessment of working memory and the NEPSY-II Auditory Response subtest. The risks for
impaired academic performance (Z ≤ −1) on components of the WIAT-III (Word Reading,
Pseudoword Decoding, and Spelling) were 2-to-3 times higher in this group than among ELGANs
not classified as having ADHD symptoms.

Conclusion—Among children born extremely preterm, those with ADHD symptoms are more
Author Manuscript

likely than others to have global neurocognitive impairment. Even when IQ is within normal
limits, ADHD symptoms are associated with deficits in executive functioning skills including
working memory, inhibition, and cognitive flexibility. These findings highlight a group at risk for
executive functioning deficits and related academic difficulties, even in the absence of intellectual
disability.

Keywords
Extreme Prematurity; Extremely Low Gestational Age Newborns; Attention Deficit Hyperactivity
Disorder; ADHD; Neuropsychological outcomes

INTRODUCTION
Author Manuscript

Compared to children born at term, those born before the 28th week gestation are at greater
risk for a range of developmental problems including neurosensory disorders, global
intellectual disability, and difficulties with aspects of broader cognition, academic
achievement, and behavior (2–4). Even when controlling for IQ or vocabulary, children born
extremely prematurely exhibit deficits in several domains of neuropsychological
functioning, including attention, executive function, visual-spatial and perceptual analysis
abilities, visual-motor skills, and memory, as well as in academic achievement (6–9).

These high-risk children are more likely than others to have attention and social problems at
early school age (ages 5 and 6 years) (10–13) and are more likely to be diagnosed with
Attention Deficit Hyperactivity Disorder (ADHD) in early childhood (13–16). With some
exceptions, (13,16) most studies indicate that the inattentive subtype of ADHD is more
Author Manuscript

common than the hyperactive/impulsive subtype among children born very preterm (17–20).
Despite the uniform findings of higher rates of ADHD in extremely preterm children
compared to the general population, little is known about the neurocognitive limitations that
accompany ADHD in these high-risk children.

ADHD is associated with poor academic outcomes and comorbid disorders/diseases/

conditions. For example, 45% of children who have ADHD also have a learning disability
(21–23) and are more likely than others to repeat a grade, have lower academic achievement,

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 3

and higher rates of dropping out of high school (24, 25). They are also more likely to need
Author Manuscript

more academic support and special education services (24, 25).

About one half of children with ADHD exhibit deficits in a range of executive abilities, most
prominently in sustained attention, response inhibition, working memory, and planning (26–
31). Children with ADHD and working memory deficits have poorer academic outcomes
including lower scores on measures of reading and math achievement as well as increased
risk for grade retention and special services (32). While the specificity of executive
functioning weaknesses in ADHD remains a topic of debate, the occurrence of deficits in
these core problem-solving skills arguably serve as a defining feature of ADHD (26).

The ELGAN Study, which enrolled infants born before the 28th week of gestation and
assessed their behavioral and neurocognitive characteristics at age 10 years, provided an
opportunity to investigate the neurocognitive correlates of ADHD symptoms in a high risk
Author Manuscript

sample of extremely low gestational age children. The primary aim of our analyses was to
evaluate the association of ADHD symptoms in extremely low gestational age newborns
(ELGANs) with the following outcomes: global cognitive ability, executive functions,
language abilities, visual-spatial skills, and academic achievement. These associations are
evaluated in the context of maternal, newborn, and educational variables.

METHODS
Participants
The ELGAN study is a multi-center prospective, observational study of the risk of structural
and functional neurologic disorders in extremely preterm infants (33). A total of 1506
infants born before the 28th week of gestation were enrolled during the years 2002–2004 and
Author Manuscript

1200 survived to 2 years, when 1102 returned for a developmental assessment (34).

At age 10 years, 889 (92%) of 966 children who were actively recruited for follow-up
(because of the availability of data on inflammation-related proteins in blood samples from
their first postnatal month), returned for an age-appropriate assessment of cognition,
executive function, behaviors, and achievement. The 871 for whom we have CSI-4 report
from a parent constitute the sample for this report (Supplemental Digital Content 1). 634
also had a teacher-completed CSI-4.

The institutional review boards of all participating institutions approved enrollment and
consent procedures for this follow up study.

Demographic and pregnancy variables

Author Manuscript

After delivery, a trained research nurse interviewed each mother in her native language using
a structured data collection form and following procedures defined in a manual. The mother
provided information regarding her own characteristics and exposures as well as the
sequence of events leading to preterm delivery.

Shortly after the mother’s discharge, the research nurse reviewed the maternal chart using a
second structured data collection form. The medical record was relied on for events

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 4

following admission. The clinical circumstances that led to preterm delivery were
Author Manuscript

operationally defined using both data from the maternal interview and data abstracted from
the medical record (35). Each mother/infant pair was assigned to the category that described
the primary reason for the preterm delivery.

Newborn variables
The gestational age estimates were based on a hierarchy of the quality of available
information. Most desirable were estimates based on the dates of embryo retrieval or
intrauterine insemination or fetal ultrasound before the 14th week (62%). When these were
not available, reliance was placed sequentially on a fetal ultrasound at 14 or more weeks
(29%), LMP without fetal ultrasound (7%), and gestational age recorded in the log of the
neonatal intensive care unit (1%).

The birth weight Z-score is the number of standard deviations the infant’s birth weight is
Author Manuscript

above or below the median weight of infants at the same gestational age in referent samples
not delivered for preeclampsia or fetal indications (36,37).

Procedures for the assessments at age 10 years

All families who participated in the previous follow up were contacted by mail and then by
phone to invite them to participate in the 10-year follow up. Lost to follow-up families were
searched for on state vaccination registries, and other openly available websites. Facebook
was also used where approved by the local institution’s IRB.

Families willing to participate were scheduled for one visit during which all of the measures
reported here were administered in fixed order in 3 to 4 hours, including breaks. The
assessments were selected to provide the most comprehensive information about
Author Manuscript

neurocognitive and academic function in one testing session. While the child was tested, the
parent or caregiver completed questionnaires regarding the child’s medical and neurological
status and behavior.

Behavioral Measures
Child Symptom Inventory-4—The parent or caregiver completed the Child Symptom
Inventory, Fourth Edition Parent Checklist (CSI-4) (38,39). The child’s current teacher was
also asked to complete the CSI-4 Teacher Checklist. Both include the same 18 items specific
for ADHD symptoms (9 for the inattentive domain and 9 for the hyperactive/impulsive
domain) that are each rated on a scale from 0 (never) to 3 (very often). Classifications
regarding significant ADHD symptoms were made based on norm-based cut-off scores
provided in the CSI-4 manual. Though severity of impairment was not directly assessed,
Author Manuscript

research suggests that classifications based on CSI-4 norm-based cut-off scores do not
significantly differ from physician provided DSM-IV and ICD-10 based diagnoses (40).

Defining classification based on symptoms identified by two informants satisfied one of the
DSM-5 criteria for ADHD. Importantly, these participants were not considered to meet
diagnostic criteria, but rather research classification of significant ADHD symptom
presentation. In order to parallel clinical decision-making, we considered three possible

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 5

contexts in which ADHD symptoms were present. Two of the contexts were taken from the
Author Manuscript

parent and teacher ADHD symptoms as reported on the CSI-4. A third context was based on
the parent’s indication at interview of the child having been diagnosed previously by a
clinician to have ADHD. Physician assessment of ADHD precedes treatment with
stimulants, and the physician’s diagnosis of ADHD is typically based equally or more on
parent and teacher report than their own observations (41) so we regarded this as pertinent to
our research classification. Participants were included in the ADHD symptom group if they
meet criteria in any two of the three contexts.

Neurocognitive measures
General cognitive ability—General cognitive ability (or IQ) was assessed with the
School-Age Differential Ability Scales, Second Edition (DAS-II) Verbal and Nonverbal
Reasoning scales (42).
Author Manuscript

Maternal cognitive ability—Maternal cognitive ability was assessed with the Kaufman
Brief Intelligence Test-Second Edition (KBIT-2).

Language ability—Expressive and receptive language skills were evaluated with the Oral
and Written Language Scales (OWLS), which assess semantic, morphological, syntactic,
and pragmatic production and comprehension of elaborated sentences (43).

Attention and executive function—We assessed attention and executive functioning

with both the DAS-II (42) and the NEPSY-II (A Developmental NEuroPSYchological
Assessment, Second Edition) (44). The DAS Recall of Digits Backward and Recall of
Sequential Order measured verbal working memory, while the NEPSY-II Auditory Attention
and Response Set measured auditory attention, set switching and inhibition, the Inhibition
Author Manuscript

and Switching scores from the NEPSY-II Inhibition subtest measured simple inhibition and
inhibition in the context of set shifting, respectively, and the NEPSY-II Animal Sorting
measured visual concept formation and set shifting. Speed of processing was assessed with
NEPSY-II Inhibition Naming, which provides a baseline measure of processing speed and
has no inhibitory component.

Latent profile analysis (LPA) was utilized to categorize extremely preterm children in the
ELGAN cohort based on the severity of their limited performance on a number of cognitive
measures (DAS-II: Verbal Reasoning, Nonverbal Reasoning, & Working Memory Clusters;
NEPSY-II: Animal Sorting, Auditory Attention, Response Set, Inhibition: Inhibition, &
Inhibition: Switching subtests). With LPA, we identified four subgroups corresponding to
functioning on measures of IQ and executive functioning: normal (34% of cohort), low-
Author Manuscript

normal (41%), moderately impaired (17%), and severely impaired (8%) (Unpublished).
Children in the moderately and severely impaired groups exhibited more global deficits
across both cognitive and executive functioning measures, whereas the low-normal group
exhibited more significant deficits in inhibition (Unpublished).

Visual perception and fine motor function—Visual perception was assessed with
NEPSY-II Arrows and Geometric Puzzles, while fine-motor function was measured with
NEPSY-II Visuomotor Precision.

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 6

Academic Function—The Wechsler Individual Achievement Test-III (WIAT-III) provides

Author Manuscript

standard scores in word recognition and decoding, spelling, and numeric operations (45).
Scores were generated based on age-based normative data.

Data Analyses
We evaluated the null hypothesis that ELGANs who had significant ADHD symptoms are
not at increased risk of neurocognitive impairment, including executive dysfunction, or
academic delays. We began our analyses by exploring the distribution of Z-scores of each
assessment separately in those with and without significant ADHD symptoms. To allow for
the differences in age at the time of the assessment, and to facilitate a comparison of our
findings to those reported for children presumably born very near term, we used Z-scores
based on distributions of values reported for the historical normative samples that are
described by the authors of the assessments we used (42–45). We then created logistic
Author Manuscript

regression models of the risk of a score one or more standard deviations below the normative
mean of each assessment. These models, which included potential confounders (including
sex, birth weight Z-score < −1, and mother’s eligibility for government-provided medical-
care insurance), allowed us to calculate odds ratios (and 95% confidence intervals) of each
10-year characteristic associated with any ADHD symptom classification.

RESULTS
Sample Characteristics (Supplemental Digital Content 2)
Teacher-completed CSI-4 forms were available for 634 of the 871 children for whom we had
a parent-completed CSI-4 form. The children whose teacher did not provide a CSI-4 report
differed minimally from the children whose teacher did return a completed form. Similarly,
the socio-demographic characteristics of their mothers also differed minimally. Differences
Author Manuscript

between the two groups were examined for statistical significance using 2-sided Fisher’s
exact test. Across maternal characteristics, perinatal characteristics, and newborn
characteristics, differences were seen at the p<0.05 level in race and gestational age.

Table 1 describes the sample characteristics in relation to combinations of observer reports

of ADHD symptoms providing a context in which to view our results. Sample characteristics
based on combinations of information sources do not differ appreciably and thus our results
do not depend on the operational definition we used for ADHD.

Intelligence, Language, and Academic Achievement Characteristics (Figure 1;

Supplemental Digital Content 3a)
The median Z-scores on all tests for children classified as having significant ADHD
Author Manuscript

symptoms were approximately −1.0 and were consistently .25 to .75 standard deviations
below the scores for children not classified as having significant ADHD symptoms.

Children with a classification of ADHD symptoms were much more likely than those
without ADHD symptoms to have low IQ scores. For example, a total IQ Z-score ≤ −2 was
found in 23% of children with ADHD symptoms but only 12% of those without ADHD

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 7

symptoms, and a verbal IQ Z-score ≤ −2 was found in 27% of children with ADHD
Author Manuscript

symptoms but only 14% of those without ADHD symptoms.

Similarly, 26% of children with a classification of ADHD symptoms had an OWLS

Listening Comprehension Z-score of ≤ −2 compared to 16% of their peers, while 30% of
children with a classification of ADHD symptoms had an OWLS Oral Expression Z-score of
≤ −2 compared to 16% of the children who did not meet criteria for ADHD symptom
classification. This almost doubling of the frequency of low scores associated with ADHD
symptom classification was also seen for each of the four WIAT-III components.

Executive Function, Processing Speed, Visual Perception, Fine-Motor Characteristics

(Figure 1; Supplemental Digital Content 3b)
The DAS-II Working Memory subtest and five of the NEPSY-II subtest scores (e.g.,
Auditory Attention, Auditory Response Set, Inhibition and Switching from the Inhibition
Author Manuscript

subtest, and Animal Sorting) assess components of executive function. Children with a
classification of ADHD symptoms had a doubling of the frequency of Z-scores of ≤ −2 on
the DAS-II Working Memory assessments, while the multiples of increased frequencies of
Z-scores of ≤ −2 were more modest on the NEPSY-II items (1.6 for Auditory Response Set
and Inhibition Switching, and 1.4 for NEPSY-II Auditory Attention, Inhibition, and Animal
Sorting). Even with the assessment of fine-motor function (NEPSY-II Visuomotor Precision
subtest) the multiple was 1.8, while the multiple dropped to 1.5 for the assessments of visual
perception (NEPSY-II Arrows and Geometric Puzzles).

Forest plots of odds ratios and 95% confidence intervals of a Z-score ≤ −1 on each DAS-II,
OWLS, WIAT-III, and NEPSY-II neurocognitive assessment associated with ADHD
symptoms (Figure 2)
Author Manuscript

In these forest plots, the large dark circles and the smaller lighter circles mark are the point
estimates of the odds ratios and the vertical ends of the horizontal lines that run through the
circles identify the lower and upper ends of the 95% confidence intervals (46). The vertical
line marks the null, an odds ratio of 1.0. When the lower end of a confidence interval does
not include 1.0, the odds ratio, marked with a large dark circle, is statistically significantly
different from 1.0 at p < 0.05.

After adjusting for three maternal characteristics (identification as black, age < 21 years, and
eligibility for government-provided medical care insurance), and three newborn
characteristics (male sex, gestational age 23–24 weeks, and birth weight Z-score < −2), an
ADHD symptom classification was significantly associated with Z-scores ≤ −1 on all DAS-
II, OWLS, and WIAT-III subtests, on all but two NEPSY-II subtests, and for LPA-based
Author Manuscript

level of executive function impairment.

To address the possibility that IQ, and not ADHD symptoms, is responsible for these
findings, we re-analyzed our data after excluding the 68 children with potential intellectual
disabilities (i.e., IQ < 70) as well as after excluding the data of children with IQ < 85 in
order to focus on children whose cognitive abilities are broadly average to above average.
After eliminating the children with IQ < 70, the ADHD-associated adjusted risk of a Z-score
≤ −1 was essentially unchanged for WIAT-III Word Reading, Pseudoword Decoding, and

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 8

Spelling, DAS-II Working Memory, and NEPSY-II Auditory Response and Visuomotor
Author Manuscript

Precision, and for LPA-based level of executive function impairment. For all other subtests,
there was no longer a significant association of a Z-score ≤ −1 with ADHD symptom
classification, when the sample was restricted to children with IQ > 70. Similarly, after
eliminating the children with IQ < 85, the ADHD-associated adjusted risk of a Z-score ≤ −1
was essentially unchanged for WIAT-III Word Reading, Pseudoword Decoding, and
Spelling, DAS-II Working Memory, and NEPSY-II Auditory Response, and for LPA-based
level of executive function impairment. Interestingly, NEPSY-II Visuomotor Precision was
no longer associated with ADHD symptoms, though NEPSY-II Geometric Puzzles indicated
some visual spatial analysis challenges in this group.

DISCUSSION
Three of our main findings are worthy of comment. First, relative to normative expectations,
Author Manuscript

the distribution of IQ scores was shifted downward across the entire ELGAN sample, and
this shift was much more prominent for ELGANs with ADHD symptom classification than
for their peers. Second, children who meet classification for ADHD symptoms are at
increased risk for many neurocognitive limitations, especially in regard to executive function
and visual-motor skills. These limitations are evident even in the subsample restricted to
children whose IQ ≥ 70 as well as in the subsample of children whose IQ ≥ 85, although less
severely than in the entire sample. Thus, we show that low IQ in ELGANs can account for a
sizable proportion of ADHD-associated limitations, but not all. Third, ELGANs with ADHD
symptoms are at an increased risk for poor performance on assessments of school
achievement in contrast with ELGANs without ADHD symptoms, with difficulties observed
across reading, spelling, and math.
Author Manuscript

Our finding of a downward shift of the IQ distribution in such a low gestational age sample
is a replicates previous findings from very preterm and/or low birth weight cohorts (47), but
in an extremely preterm cohort. To minimize the potential contribution of low IQ to our
understanding of impaired neuropsychological function, we restricted some analyses to
children whose IQs were ≥ 70 as well as to children whose IQs were ≥ 85. Even then,
children classified as having ADHD symptoms were more likely than their peers to have
specific deficits on the DAS-II working memory and NEPSY-II Auditory Response. In those
with IQs ≥ 70 specific deficits in NEPSY-II Visuomotor Precision were identified, however,
these deficits were not seen in the group with IQs ≥ 85 though deficits on NEPSY-II
Geometric Puzzles were identified in this group. Across both groups, ADHD symptoms
were associated with LPA-defined moderate impairment and low normal function again
supporting our findings that both IQ and executive functioning are areas of concern in
Author Manuscript

ELGANs with significant ADHD symptoms. ELGANs in the LPA-defined Low Normal
group have significant challenges in aspects of executive functioning (specifically inhibition)
as compared to performance on measures of verbal and nonverbal IQ (Unpublished).
Overall, these results are consistent with previous studies that have identified significant
deficits in attention, working memory, executive function, and visuomotor and visual spatial
skills, beyond the generalized cognitive weaknesses seen in children born extremely preterm
(9, 48–51). Moreover, the deficits we found on the DAS-II working memory and NEPSY-II
Auditory Response tasks, which require sustained and dual attention, working memory,

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 9

inhibitory control, and cognitive flexibility, were present even after adjusting for key
Author Manuscript

sociodemographic and medical variables.

In the general population, (26, 27, 28, 29) and in children born preterm or at low birth
weight (52, 53,13), those with ADHD exhibit deficits in a range of executive abilities. In a
meta-analysis, groups with ADHD exhibited significant impairment across executive
functioning tasks compared to those without ADHD, with the strongest effect sizes
identified on measures of response inhibition, vigilance, working memory, and planning
(54). While there remains some debate regarding the specificity of executive function
weaknesses in ADHD, it is clear that the two are associated (31). Among children born
preterm who do not necessarily meet criteria for ADHD, frequently reported executive
dysfunction includes challenges with working memory, visual attention, and set shifting (29,
53). When examining neuropsychological correlates, relationships between behavioral
ratings of ADHD symptoms and poorer performances on measures of rapid naming, set
Author Manuscript

shifting, and focused and sustained attention have been identified in a cohort of children
with extreme prematurity (29). Similarly, performance on neuropsychological measures of
attention and executive functioning is correlated with parent and teacher report of ADHD
symptoms in a more recent extreme prematurity cohort (53). Given the significant
heterogeneity in executive dysfunction found among individuals with ADHD (31), the
finding that cognitively intact ELGANs (IQ>70 and IQ>85) with ADHD symptoms are at
significantly increased risk for deficits in working memory, inhibition, and cognitive
flexibility strongly suggests that, within this population, there is a higher co-occurrence of
these deficits than in the typical ADHD profile. While ADHD symptoms and executive
function are associated, specific domains of executive dysfunction that are associated with
ADHD are less clear, and may vary by age, executive functions assessed, and population
evaluated. Nonetheless, these results help support previous findings of deficits in working
Author Manuscript

memory and set-shifting in ELGANs who have ADHD symptoms, and add to the literature
by identifying an association with inhibition as well.

In ELGANs, delays in early motor development at 2.5 years predict inattention at age 11
years (55). Our results suggest that motor delays are not simply a predictor of inattentive
symptoms, but that children with ADHD symptoms are more likely than others to have
persistent difficulties with visuomotor coordination.

Finally, we found that children who had an ADHD symptom classification are at
significantly increased risk for poor academic outcomes, even in the subsample of children
whose IQ was > 70 and >85. These findings highlight the cumulative impact of attention and
executive function deficits on learning and academic development among children born very
Author Manuscript

(56) or extremely preterm (57). Improved academic function might require a multifaceted
intervention in this population

This study has several limitations. First, we did not receive teacher ratings for 237 of the 871
children for whom we did receive parent ratings. The missing data limited the number of
children who could have reports from two observers (usually parent and teacher, although
occasionally teacher and physician). We are uncertain about the potential bias. Second, we
did not utilize a standardized or conventional diagnostic instrument to assess ADHD

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 10

presentation (59). Although the CSI-4 appears attractive in light of its orientation to DSM-5,
Author Manuscript

there are limits to this measure as is the case with many parent or teacher report
questionnaires assessing ADHD symptoms. This limited our ability to assess the
psychometric properties and reliability of the CSI-4 ratings. The CSI-4 was used principally
to assess ADHD symptom presentation, which did not provide a scale of functional
impairment as is required for diagnostic decision making. We did not obtain information
about the severity of each participants ADHD symptoms. The validity of the CSI-4 for
diagnosis of ADHD has not been adequately assessed (60, 61). Despite these weaknesses, a
recent study of ADHD diagnoses in a pediatric population in central and eastern Europe and
Asia indicated that ADHD classifications based on CSI-4 norm-based cut-off scores did not
significantly differ from physician provided DSM-IV and ICD-10 based diagnoses (40).
Third, although the CSI-4 does generate ADHD subtyping information we were not able to
take advantage of this because of the high rate of disagreement about subtype even when the
Author Manuscript

reporters agreed on the presence of ADHD. We did utilize physician diagnosis in defining
our ADHD symptom group. We do not know to what extent the physician’s diagnosis of
ADHD is based on personal observation and therefore provides independent information, or
provides redundant information because it was based on parent and teacher reports. Because
some of the physicians’ diagnoses may have been made years earlier, the physicians have, in
essence, provided “life-time” diagnoses, whereas both teacher and parent provided
information about current symptoms. Although we were able to document the working
memory, inhibition, and switching limitations of children identified to have ADHD
symptoms, we did not assess the effect of executive dysfunction on activities of daily life. It
will be helpful for future assessments of the neuropsychological correlates of ADHD
symptoms to more directly assess executive dysfunction within the context of daily life, as
reported by parents and teachers, through the inclusion of questionnaires to directly assess
day-to-day executive functioning (e.g., the Behavior Rating Inventory of Executive
Author Manuscript

Function-2). Our comparison group is based on data from a national-based normative

sample rather than full-term sibling paired controls. We acknowledge that we cannot
separate the impact of ADHD symptoms on test performance from the very dysfunctions we
assessed. Finally, it will be important for future research to examine possible mitigating
factors on ADHD behaviors and neuropsychological functioning in this population such as
medication response or receipt of early intervention, behavioral, or academic services.

Our study has several strengths. First, we included a large number of children, making it
unlikely that we have missed important associations due to lack of statistical power, or
claimed associations that might reflect the instability of small numbers of participants.
Second, we selected infants based on gestational age, not birth weight, in order to minimize
confounding due to factors related to fetal growth restriction (17). Third, we collected all of
Author Manuscript

our data prospectively. Fourth, attrition was modest, limiting the resultant bias.

Conclusions
Among children born extremely preterm, those who were classified as having ADHD
symptoms had lower IQs and lower scores on assessments of executive function indicators
than those not considered to have ADHD symptoms. These children are at substantial risk
for academic underachievement even when intellectual abilities are within normal limits.

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 11

This places them at particular risk in the classroom, because these neurocognitive deficits
Author Manuscript

likely will interfere with learning, accessing information, and perhaps behavior. Our findings
add to the growing literature on neurocognitive outcomes of extreme prematurity and
highlight the need for early identification of and intervention to limit adverse consequences.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
This study was supported by The National Institute of Neurological Disorders and Stroke (5U01NS040069-05, and
2R01NS040069 - 06A2), and the National Institute of Child Health and Human Development (5P30HD018655-34).
The authors also gratefully acknowledge the contributions of their subjects, and their subjects’ families, as well as
those of their colleagues.
Author Manuscript

Source Funding: Scott J. Hunter, Ph.D. receives royalties from Cambridge University Press and is funded through
grants (PAR-12-068 Fogarty HIV Research Training Program for Low and Middle Income Country Institutions
(D43); NIH-NIDDK R03 DK103096-01; NIH-NICHD R01 HD074757).

References
1. Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the
NICHD Neonatal Research Network. Pediatrics. 2010; 126:443–456. [PubMed: 20732945]
2. Anderson PJ. Neuropsychological outcomes of children born very preterm. Semin Fetal Neonatal
Med. 2014; 19:90–96. [PubMed: 24361279]
3. Moreira RS, Magalhães LC, Alves CR. Effect of preterm birth on motor development, behavior, and
school performance of school-age children: a systematic review. J Pediatr. 2014; 90:119–34.
4. Johnson S. Cognitive and behavioural outcomes following very preterm birth. Semin Fetal Neonatal
Med. 2007; 12:363–373. [PubMed: 17625996]
Author Manuscript

5. Orchinik LJ, Taylor HG, Espy KA, et al. Cognitive outcomes for extremely preterm/extremely low
birth weight children in kindergarten. J Int Neuropsychol Soc. 2011; 17:1067–1079. [PubMed:
21923973]
6. Taylor HG, Klien N, Anselmo MG, et al. Learning problems in kindergarten students with extremely
preterm birth. Arch Pediatr Adolesc Med. 2011; 165:819–825. [PubMed: 21893648]
7. Aarnoudse-Moens CSH, Weisglas-Kuperus N, van Goudoever JB. Meta-analysis of neurobehavioral
outcomes in very preterm and/or very low birth weight children. Pediatrics. 2010; 124:717–728.
8. Bayless S, Stevenson J. Executive functions in school-age children born very prematurely. Early
Hum Dev. 2007; 83:247–254. [PubMed: 16837146]
9. Joseph RM, O’Shea TM, Allred EN, et al. ELGAN Study Investigators. Neurocognitive and
Academic Outcomes at Age 10 Years of Extremely Preterm Newborns. Pediatrics. 2016; 137:pii:
e20154343.
10. Sykes DH, Hoy EA, Hill JM, et al. Behavioural adjustment in school of very low birthweight
children. J Child Psychol Psychiatry. 1997; 38:315–325. [PubMed: 9232478]
11. Clark CAC, Woodward LJ, Horwood LJ, et al. Development of emotional and behavioral
Author Manuscript

regulation in children born extremely preterm and very preterm: Biological and social influences.
Child Dev. 2008; 79:1444–1462. [PubMed: 18826535]
12. Spittle AJ, Treyvaud K, Doyle LW, et al. Early Emergence of behavior and social-emotional
problems in very preterm infants. J Am Acad Child Adolesc Psychiatry. 2009; 48:9099–18.
13. Scott MN, Taylor HG, Fristad MA, et al. Behavior disorders in extremely preterm/extremely low
birth weight children in kindergarten. J Dev Behav Pediatr. 2012; 33(3):202–13. [PubMed:
22245934]
14. Aylward GP. Neurodevelopmental outcomes of infants born prematurely. J Dev Behav Pediatr.
2005; 26:427–40. [PubMed: 16344661]

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 12

15. Delobel-Ayoub M, Kaminski M, Marret S, et al. Behavioral outcome at 3 years of age in very
preterm infants: the EPIPAGE study. Pediatrics. 2006; 117:1996–2005. [PubMed: 16740841]
Author Manuscript

16. Reijneveld SA, de Kleine MJK, van Baar AL, et al. Behavioural and emotional problems in very
preterm and very low birthweight infants at age 5 years. Arch Dis Child Fetal Neonatal Ed. 2006;
91:F423–28. [PubMed: 16877476]
17. Hack M, Taylor HG, Schluchter M, et al. Behavioral outcomes of extremely low birth weight
children at age 8 years. J Dev Behav Pediatr. 2009; 30:122–130. [PubMed: 19322106]
18. Johnson S, Hollis C, Kochhar P, et al. Psychiatric disorders in extremely preterm children:
longitudinal finding at age 11 years in the EPICure study. J Am Acad Child Adolesc Psychiatry.
2010; 49(5):453–63 e1. [PubMed: 20431465]
19. Johnson S, Marlow N. Growing up after extremely preterm birth: lifespan mental health outcomes.
Semin Fetal Neonatal Med. 2014; 19(2):97–104. [PubMed: 24290907]
20. Anderson PJ, De Luca CR, Hutchinson E, et al. Attention problems in a representative sample of
extremely preterm/extremely low birth weight children. Dev Neuropsychol. 2011; 36(1):57–73.
[PubMed: 21253991]
21. Seidman LJ, Biederman J, Valera EM, et al. Neuropsychological functioning in girls with
Author Manuscript

attention-deficit/hyperactivity disorder with and without learning disabilities. Neuropsychology.

2006; 20:166–177. [PubMed: 16594777]
22. Seidman LJ. Neuropsychological functioning in people with ADHD across the lifespan. Clin
Psychol Rev. 2006; 26:466–485. [PubMed: 16473440]
23. DuPaul GJ, Gormley MJ, Laracy SD. Comorbidity of LD and ADHD: implications of DSM-5 for
assessment and treatment. J Learn Disabil. 2013; 46(1):43–51. [PubMed: 23144063]
24. Biederman J, Faraone SV, Mick E, et al. Clinical correlates of ADHD in females: findings from a
large group of girls ascertained from pediatric and psychiatric referral sources. J Am Acad Child
Adolesc Psychiatry. 1999; 38(8):966–975. [PubMed: 10434488]
25. Barbaresi WJ, Katusic SK, Colligan RC, et al. Long-term school outcomes for children with
attention-deficit/hyperactivity disorder: a population-based perspective. J Dev Behav Pediatr. 2007;
28(4):265–273. [PubMed: 17700078]
26. Nigg JT, Blaskey LG, Stawicki JA, et al. Evaluating the endophenotype model of ADHD
neuropsychological deficit: Results for parents and siblings of children with ADHD combined and
Author Manuscript

inattentive subtypes. J Abnorm Psychol. 2004; 113:614–625. [PubMed: 15535793]

27. Pennington BF, Ozonoff S. Executive functions and developmental psychopathology. J Child
Psychol Psychiatry. 1996; 37:51–87. [PubMed: 8655658]
28. Willcutt EG, Doyle AE, Nigg JT, et al. Validity of the executive function theory of attention-deficit/
hyperactivity disorder: A meta-analytic review. Biol Psychiatry. 2005; 57:1336–1346. [PubMed:
15950006]
29. Taylor HG, Hack M, Klein NK. Attention deficits in children with <750 gm birth weight. Child
Neuropsychol. 1998; 4:21–34.
30. Shum D, Neulinger K, O’Callahan M, et al. Attentional problems in children born very preterm or
with extremely low birth weight at 7–9 years. Arch Clin Neuropsych. 2008; 23:103–112.
31. Nigg JT, Willcutt EG, Doyle, et al. Causal heterogeneity in attention-deficit/hyperactivity disorder:
do we need neuropsychologically impaired subtypes? Biol Psychiatry. 2005; 57(11):1224–1230.
[PubMed: 15949992]
32. Fried R, Chan J, Feinberg L, et al. Clinical correlates of working memory deficits in youth with
and without ADHD: a controlled study. J Clin Exp Neuropsyc. 2016; 38(5):487–496.
Author Manuscript

33. O’Shea TM, Allred EN, Dammann O, et al. The ELGAN study of the brain and related disorders in
extremely low gestational age newborns. Early Hum Dev. 2009; 85:719–725. [PubMed:
19765918]
34. Helderman JB, O’Shea TM, Goldstein DJ, et al. Antenatal antecedents of low scores on the Bayley
Scales of Infant Development at 24 months among children born before the 28th post-menstrual
week. The ELGAN Study. Pediatrics. 2012; 129(3):494–502. [PubMed: 22331342]
35. McElrath TF, Hecht JL, Dammann O, et al. Pregnancy disorders that lead to delivery before the
28th week of gestation: an epidemiologic approach to classification. Am J Epidemiol. 2008;
168:980–9. [PubMed: 18756014]

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 13

36. Yudkin PL, Aboualfa M, Eyre JA, et al. New birthweight and head circumference centiles for
gestational ages 24 to 42 weeks. Early Hum Dev. 1987; 15(1):45–52. [PubMed: 3816638]
Author Manuscript

37. Leviton A, Paneth N, Reuss ML, et al. Maternal infection, fetal inflammatory response, and brain
damage in very low birthweight infants. Pediatr Res. 1999; 46(5):566–75. [PubMed: 10541320]
38. Sprafkin J, Gadow KD, Salisbury H, et al. Further evidence of reliability and validity of the Child
Symptom Inventory-4: parent checklist in clinically referred boys. J Clin Child Adolesc. 2002;
31(4):513–24.
39. Gadow, KD., Sprafkin, J. Child Symptom Inventory–4 Screening and Norms Manual. Stony Brook,
NY: Checkmate Plus; 2002.
40. Martenyi F, Treuer T, Gau SS, et al. Attention-deficit/hyperactivity disorder diagnosis, co-
morbidities, treatment patterns, and quality of life in a pediatric population in central and eastern
europe and asia. J Child Adolesc Psychopharmacol. 2009; 19(4):363–376. [PubMed: 19702488]
41. Power TJ, Mautone JA, Manz PH, et al. Managing attention-deficit/hyperactivity disorder in
primary care: a systematic analysis of roles and challenges. Pediatrics. 2008; 121(1):e65–72.
[PubMed: 18166546]
42. Elliott, CD. Differential Ability Scales. 2nd. San Antonio, TX: Pearson; 2007.
Author Manuscript

43. Carrow-Woolfolk, E. Oral and Written Language Scales: Written Expression Scale Manual. Circle
Pines, MN: American Guidance Service; 1996.
44. Korkman, M., Kirk, U., Kemp, S. NEPSY: A Developmental Neuropsychological Assessment.
New York: The Psychological Corporation; 1998.
45. Wechsler, D. The Wechsler Individual Achievement Test-III. Oxford, UK: Pearson Assessment;
2009.
46. Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. Brit Med J. 2001; 322(7300):
1479–1480. [PubMed: 11408310]
47. Hack M, Taylor G, Klein N, et al. School-age outcomes in children with birth weights under 750g.
N Engl J Med. 1994; 331:753–759. [PubMed: 7520533]
48. Taylor HG, Minich N, Bangert B, et al. Long-term neuropsychological outcomes of very low birth
weight: Associations with early risks for periventricular brain insults. J Int Neuropsychol Soc.
2004; 10:987–1004. [PubMed: 15803562]
49. Taylor HG, Klein N, Drotar D, et al. Consequences of <1000-g birth weight for neuropsychological
Author Manuscript

skills, achievement, and adaptive functioning. J Dev Behav Pediatr. 2006; 27:459–469. [PubMed:
17164618]
50. Orchinik LJ, Taylor HG, Espy KA, et al. Cognitive outcomes for extremely preterm/extremely low
birth weight children in kindergarten. J Int Neuropsychol Soc. 2011; 17:1067–1079. [PubMed:
21923973]
51. Kulseng S, Jennekens-Schinkel A, Naess P, et al. Very-low-birthweight and term small-for-
gestational-age adolescents: Attention revisted. Acta Paediatr. 2006; 95:224–230. [PubMed:
16449031]
52. Nedeau L, Boivin M, Tessier R, et al. Mediators of behavioral problems in 7-year-old children born
after 24 to 28 weeks of gestation. J Dev Behav Pediatr. 2001; 22:1–10. [PubMed: 11265917]
53. Shum D, Neulinger K, O’Callaghan M, et al. Attentional problems in children born with very
preterm or with extremely low birth weight at 7–9 years. Arch Clin Neuropsych. 2008; 23:103–
112.
54. Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF. Validity of the executive function
theory of attention-deficit/hyperactivity disorder: A meta-analytic review. Biological Psychiatry.
Author Manuscript

2005; 57:1336–1346. [PubMed: 15950006]

55. Edwards J, Berube M, Erlandson K, et al. Developmental coordination disorder in school-aged
children born very preterm and/or at very low birth weight: A systematic review. J Dev Behav
Pediatr. 2011; 32:678–687. [PubMed: 21900828]
56. Johnson S, Kochhar P, Hennessy E, et al. Antecedents of attention-deficit/hyperactivity disorder
symptoms in children born extremely preterm. J Dev Behav Pediatr. 2016; 37:285–297. [PubMed:
27096570]

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 14

57. Jaekal J, Wolke D, Bartmann P. Poor attention rather than hyperactivity/impulsivity predicts
academic achievement in very preterm and full-term adolescents. Psychol Med. 2013; 43:183–196.
Author Manuscript

[PubMed: 22608065]
58. Aarnoudse-Moens CSH, Weisglas-Kuperus N, Duivenvoorden J, et al. Executive function and IQ
predict mathematical and attention problems in very preterm children. PLoS ONE. 2013;
8:e55994. [PubMed: 23390558]
59. Tripp G, Schaughency EA, Clarke B. Parent and teacher rating scales in the evaluation of attention-
deficit hyperactivity disorder: contribution to diagnosis and differential diagnosis in clinically
referred children. J Dev Behav Pediatr. 2006; 27:209–18. [PubMed: 16775518]
60. Sprafkin J, Gadow KD, Salisbury H, et al. Further evidence of reliability and validity of the Child
Symptom Inventory-4: parent checklist in clinically referred boys. J Clin Child Adolesc. 2002;
31:513–524.
61. Ghanizadeh A. Psychometric analysis of the new ADHD DSM-V derived symptoms. BMC
Psychiatry. 2012; 12:21. [PubMed: 22433111]
Author Manuscript
Author Manuscript
Author Manuscript

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 15
Author Manuscript
Author Manuscript
Author Manuscript

Figure 1.
Author Manuscript

Box-and-whisker plots of each neurocognitive subtest by ADHD (defined as meeting criteria

by 2 of the following: CSI-4 report by parent, CSI-4 report by teacher, or clinical diagnosis).
All subtest Z-scores are adjusted to population norms. Key: dark gray is ADHD and light
gray is Non-ADHD. The central line in the box indicates the median (50th centile), while the
top of the box indicates the 75th centile and the bottom of the box indicates the 25th centile.
V=Verbal, NV=Nonverbal reasoning, WM=Working memory, LC=Listening
comprehension, OE=Oral expression, WR=Word reading, PwD=Pseudoword decoding,

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 16

Sp=Spelling, NO=Numerical operations, AA=Auditory attention, RS=Auditory response

Author Manuscript

set, INI=Inhibition inhibition, INS=Inhibition switching, AS=Animal sorting,

INN=Inhibition naming, AW=Arrows, GEO=Geometric puzzles, VP=Visuomotor precision.
Author Manuscript
Author Manuscript
Author Manuscript

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 17
Author Manuscript
Author Manuscript
Author Manuscript

Figure 2.
Author Manuscript

Forest plots of odds ratios (ORs) and 95% confidence intervals of a Z-score ≤ –1 on each
DAS-II, OWLS, WIAT-III, and NEPSY-II neurocognitive assessment at age 10 associated
with ADHD (defined as meeting criteria by 2 of the following: CSI-4 report by parent,
CSI-4 report by teacher, or clinical diagnosis). Odds ratios in the left panel are unadjusted,
while those in the right panel are adjusted for mother’s identification as black, mother’s age
< 21 years, mother eligibility for public insurance, male sex, gestational age 23–24 weeks
and birth weight Z-score < –2. The top set of panels is for all children, while the middle set

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Scott et al. Page 18

is for children with an IQ > 70, and the bottom set is for children with an IQ > 85. Large
Author Manuscript

dark circles indicate ORs significantly different from 1.0 (p < 0.05) while smaller gray
circles indicate non-significant ORs. The ends of the horizontal lines indicate the bounds of
the 95% confidence interval.
Author Manuscript
Author Manuscript
Author Manuscript

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
 Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Table 1

Sample characteristics. Percent of children identified as having ADHD symptoms (according to the reporters identified at the top of the column) whom
also had the characteristic listed on the left.
Scott et al.

Any ADHD based on

Non-ADHD by All 3
Characteristic Parent + Teacher Parent + Physician Teacher + Physician Any 2 or All 3

Maternal
Racial identity White 8 12 9 17 82

Black 11 13 15 21 76

Other 10 10 9 13 79

Hispanic Yes 7 12 7 12 84

No 9 13 11 18 80

Age, years < 21 11 20 16 27 68

21–35 9 12 11 17 82

> 35 7 8 6 12 85

Education, years ≤ 12 12 17 15 23 75

> 12, < 16 9 11 11 16 83

≥ 16 7 10 5 13 86

Single marital Status Yes 12 16 16 22 74

No 7 10 7 14 85

Public insurance Yes 13 19 17 26 72

No 7 9 7 13 85

Newborn

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
Sex Male 13 15 14 22 75

Female 5 10 6 13 86

Gestational age, weeks 23–24 11 19 14 25 74

25–26 10 12 11 17 80

27 7 9 8 13 85

Birth weight, Grams ≤ 750 11 15 13 20 78

751–1000 7 10 8 14 83

> 1000 10 14 10 19 80
Page 19
 Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Any ADHD based on

Non-ADHD by All 3
Characteristic Parent + Teacher Parent + Physician Teacher + Physician Any 2 or All 3
Birth weight Z-score < –2 4 12 8 14 87
Scott et al.

≥ −2, < −1 10 13 8 17 81

≥ −1 9 13 10 18 80

Education
IEP Yes 14 19 17 27 71

No 3 5 3 7 92

Repeated Grade Yes 14 22 17 29 68

No 8 10 9 15 84

Remedial Class Yes 17 17 21 26 68

No 7 11 8 15 84

Current ADHD medication Yes 22 53 38 65 32

No 6 4 5 8 91

N ADHD (N total) 57 (634) 109 (871) 66 (637) 152 (874) 511 (634)

J Dev Behav Pediatr. Author manuscript; available in PMC 2018 May 01.
Page 20